Small molecule kinase inhibitors are an attractive means to modulate kinase
activities in medicinal chemistry and chemical biology research. In the
physiological setting of a cell, kinase function is orchestrated by a plethora
of regulatory processes involving the structural transition of kinases between
inactive and enzymatically competent conformations and vice versa. The
development of novel kinase inhibitors is mainly fostered by high-throughput
screening initiatives where the small molecule perturbation of the
phosphorylation reaction is measured to identify inhibitors. Such setups require
enzymatically active kinase preparations and present a risk of solely
identifying classical ATP-competitive Type I inhibitors. Here we report the
high-throughput screening of a library of approximately 35000 small organic
molecules with an assay system that utilizes enzymatically inactive human
p38alpha MAP kinase to detect stabilizers of the pharmacologically more
desirable DFG-out conformation. We used protein X-ray crystallography to
characterize the binding mode of hit compounds and reveal structural features
which explain how these ligands stabilize and/or induce the DFG-out
conformation. Lastly, we show that although some of the hit compounds were
confirmed by protein X-ray crystallography, they were not detected in classic
phosphorylation assays, thus validating the unique sensitivity of the assay
system used in this study and highlighting the potential of screening with
inactive kinase preparations.

M.Rabiller,M.Getlik,S.Klüter,A.Richters,S.Tückmantel,J.R.Simard,andD.Rauh
(2010).Proteus in the world of proteins: conformational changes in protein kinases.

Arch Pharm (Weinheim),
343,
193-206.

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